Viral Meningitis: An Overview

Teresa Chu, PhD in PharmacologyClinical LecturerSchool of Medicine, University of CaliforniaRiverside, California

4/18/2014

US Pharm. 2014(39):HS13-HS15.

ABSTRACT: Viral meningitis is the most common form of meningitis,
affecting individuals of all ages. Enteroviruses constitute the most
common host, followed by herpes simplex virus 2 (HSV-2),
varicella-zoster virus, and others. The classic symptoms of viral
meningitis—sudden onset of fever, stiff neck, and altered mental
status—are indistinguishable from those of bacterial meningitis.
Analysis of cerebrospinal fluid obtained via lumbar puncture provides a
definitive diagnosis. There is no specific treatment. Complete recovery
within 7 to 10 days is common, except in immunocompromised patients. In
addition to symptom management, antiviral agents may be used to treat
HSV-2 meningitis. The best strategy for avoiding viral meningitis is to
prevent viral infection by undergoing vaccination and practicing good
hygiene.

Meningitis is an inflammation of the membranes (dura, pia, and
arachnoid maters) covering the brain and spinal cord. Causes of
meningitis include viral, bacterial, and fungal infections, and host
factors directly affect disease progression and outcome.Viral meningitis,
a type of aseptic meningitis, is the most common form; it accounts for
about 50% of meningitis-related hospitalizations in the United States,
but most cases are self-limiting.1 In contrast, acute bacterial meningitis is a potentially fatal neurologic emergency, and survivors can have permanent neurologic complications.2 Therefore, it is critical to rapidly determine the type of meningitis during diagnosis.

Etiology and Route of Transmission

Enteroviruses (EVs) are the most common infectious agents, accounting
for up to 90% of viral meningitis cases, followed by herpes simplex
virus 2 (HSV-2) and other viruses.3-6

EVs:EV meningitis occurs sporadically, with
outbreaks commonly occurring in the summer and early fall (the
enteroviral season). The reported incidence may be underestimated, since
most cases are mild and do not require hospital admission.7 Within the EV family, coxsackieviruses and echovirusesare responsible for the majority of cases.8
Infants, young children (<5 years), and elderly persons who interact
or reside in group settings are more susceptible, but the incidence in
children tends to decrease with age.3,9 Transmission is
mediated primarily via the fecal-oral route or through respiratory
droplets and fomites (inanimate objects or substances that can carry
infectious organisms, such as utensils).3 EV meningitis can cause significant morbidity with respect to hospitalization and duration of impaired activity.4 Severe complications are uncommon, except in immunocompromised patients.7 Although rare, cases of concomitant EV meningitis and bacterial meningitis have been reported.10,11

Meningitis can occur as an uncommon neurologic complication of
enterovirus 71 (EV71), a common cause of hand-foot-mouth disease in
children. EV71 outbreaks occur periodically in the Asian Pacific
countries and rarely in the U.S.12,13

Herpesviruses:Of the three herpesviruses that
can remain latent in the host for a lifetime, herpes simplex virus 1
(HSV-1) is more associated with encephalitis, whereas HSV-2 and
varicella-zoster virus (VZV) cause meningitis.7,14 These
viruses cause primary infection of mucocutaneous surfaces, establish
latency in the peripheral sensory ganglia through retrograde
transportation, and reactivate periodically with anterograde
transmission to the nerve endings and mucocutaneous surfaces.14

HSV-2 meningitis, which is far more common than VZV meningitis, may
develop during or after a primary genital infection, which is acquired
mainly through sexual contact.14-16 Among patients with
primary genital herpes, 36% of women and 13% of men have been reported
to develop meningitis as a complication.14,17 HSV-2 meningitis can also occur without any genital herpes symptoms.18 Once a person develops HSV-2 meningitis, there is a 19% to 42% chance that meningitis will recur over his or her lifetime.19,20
A 56-year interval between the initial genital herpes infection and the
first recurrent HSV-2 meningitis episode was reported in a 78-year-old
patient.16 Recurrent benign lymphocytic meningitis (RBLM), also known as Mollaret meningitis,
is a rare disease most frequently caused by HSV-2. RBLM is
characterized by three to 10 episodes of benign meningitis that last for
2 to 5 days before spontaneous recovery.21

VZV, which causes chickenpox (varicella), may reactivate to cause
shingles (herpes zoster). Meningitis is a rare complication of primary
infection and is more common during reactivation. VZV meningitis also
may occur without cutaneous symptoms. In a study involving 21 patients
with VZV meningitis, more than 50% had no skin lesions.22 Transmission occurs mainly through direct or indirect contact with the saliva, sputum, or mucus of an infected person.3

Other HSVs associated with meningitis are cytomegalovirus (CMV),
Epstein-Barr virus (EBV), and human herpesvirus 6. Central nervous
system infections from CMV are seen mostly in immunocompromised
patients.3,8

Mumps and Measles: Mumps, a childhood infection
characterized by swelling of the parotid salivary gland, is caused by
the mumps virus. Meningitis was a common complication before the
introduction of immunization. Mumps can be spread through direct or
indirect contact with the saliva or mucus of an infected person.3 Despite routine vaccination, mumps outbreaks occurred in the Midwest in 2006, affecting mostly young adults.23Morbillivirus, which is responsible for measles, in rare cases can cause meningitis.3

HIV and Other Viruses: HIV may be a cause of viral
meningitis during seroconversion (presence of anti-HIV antibodies in
blood). The meningitis may persist in a small number of cases, and in
some instances it may be complicated by cranial neuropathies.7

Arthropod-borne viruses (arboviruses) such as West Nile virus account
for a few cases of meningitis each year, usually during the summer and
early fall, when insect populations are high.24 Lymphocytic choriomeningitis virus (LCMV), which is spread by rodents, in rare cases may cause meningitis.25 Contact with the blood, saliva, urine, droppings, or nesting materials of infected rodents can lead to transmission.

Pathogenesis

Viruses enter the brain by two major routes: hematogenous (carried by
blood) or neural (carried by nerves). Most EV infections start in the
intestine, after the individual swallows the initial inoculum, and
spread to other tissues and the blood. Brain penetration is mediated by
the hematogenous pathway. HSVs (HSV-1, HSV-2, VZV) enter the brain
mainly via the peripheral and cranial nerves. Once inside the brain, the
virus spreads through the subarachnoid space in cerebrospinal fluid
(CSF), and its rapid replication can overcome the host defenses.
Inflammatory WBCs such as lymphocytes accumulate and target the virus.
Consequently, inflammatory cytokines such as interleukin (IL)-1β, IL-6,
and tumor necrosis factor-α are released. Inflammatory responses can
increase the permeability of the blood-brain barrier, allowing the
entrance of circulating immunoglobulins.7,26

Symptoms

The classic triad of viral meningitis symptoms consists of
sudden-onset (occurring hours to 1-2 days after infection) fever, stiff
neck (nuchal rigidity), and altered mental status. Other symptoms
include nausea, vomiting, and sensitivity to light.3,8 Irritability, refusal to eat, and rash are possible symptoms in infants and young children.27

EV meningitis may be accompanied by symptoms including localized vesicles, herpangina, and generalized maculopapular rash.8 Seizures or an abrupt deterioration in mental status may indicate progression to meningoencephalitis.28
Back, buttock, perineal, or lower-extremity pain, urinary retention,
constipation, paresthesias, and motor weakness are complications of
HSV-2 meningitis.14,17 In mumps meningitis, swelling of the salivary gland is observed in about 50% of cases.7

Most symptoms of viral meningitis last from 7 to 10 days, and patients with a normal immune system usually recover completely.3

Diagnosis

Because the symptoms of viral meningitis are indistinguishable from
those of bacterial meningitis, hospitalization, empirical prescription
of antibiotics, and lumbar puncture are necessary for exclusion of
bacterial meningitis. Identification of a viral cause can reduce
antibiotic use and shorten hospital stays.6,8

Lumbar Puncture for CSF Analysis:A definitive
diagnosis is obtained by analyzing CSF collected via lumbar puncture.
Analysis includes WBC count; differential, protein, and glucose levels;
microscopy with Gram stain; and culture (TABLE 1). In contrast to
bacterial meningitis, the opening pressure and glucose level are
usually normal in viral meningitis, and the protein level is only
slightly elevated. Whilebacterial meningitis is characterized by
polymorphonuclear leukocyte (PMNL) predominance, mononuclear lymphocyte
predominance is common in viral meningitis.8,29,30 However, PMNL predominance and persistence beyond 24 hours have been observed in children with viral meningitis.31 Therefore, PMNL predominance cannot be regarded as a sole criterion for diagnosis.

Despite its high cost, polymerase chain reaction (PCR) can rapidly and accurately detect EV, HSV, VZV, and EBV.32-34 A positive PCR test can prevent unnecessary hospital admission in a patient with mild symptoms.30
EV meningitis may be difficult to differentiate from partially treated
bacterial meningitis because antibiotic treatment can lead to unreliable
Gram stain results. Therefore, many patients with viral meningitis are
treated with empirical antibiotics in the hospital until the PCR test
results are known.35

Physical Examination:Kernig’s and Brudzinski’s signs pertain to inflammation of the meninges and nerve endings.36 At one time, both were used to diagnose meningitis. Kernig’s sign is the inability to straighten the leg when the hips are flexed to a 90-degree angle; Brudzinski’s sign is the spontaneous flexion of the hips and knees during attempted flexion of the neck.Because
of individual patients’ variations in sensitivity and specificity,
these methods should be used only to supplement diagnosis.

Treatment

No specific treatment is recommended for viral meningitis, and most
patients, except for those who are immunocompromised, recover completely
on their own within 7 to 10 days.3 The main therapeutic
strategy is symptom management, including prevention of dehydration,
reduction of body temperature with antipyretics, and alleviation of pain
with analgesics.4

Variable antiviral treatment, including agents such as acyclovir and
valacyclovir, has been used for uncomplicated HSV-2 meningitis.37,38 Suppressive prophylactic therapy with acyclovir, famciclovir, and valacyclovir may help prevent the recurrence of HSV-2 RBLM.14 Patients with RBLM should be counseled regarding genital herpes and its transmission.21

Long-Term Sequelae

Recovery from viral meningitis is usually complete, although some
patients experience short-term memory loss, cognitive impairment, and
sleep disturbances after recovery.39-41 Other sequelae
include fatigue and depression, which may be related to prolonged
convalescence and previous psychiatric history.42 Infants (<1 year) with meningitis may later exhibit subtle neurodevelopmental setbacks, such as language problems.43

Compared with other forms of viral meningitis, HSV-2 meningitis
causes more neurologic complications that are likely to resolve after 6
months.19 Long-term neurologic sequelae may occur in
immunocompromised patients. Prompt treatment with acyclovir and
valacyclovir may be helpful in preventing sequelae.38

Prevention

The best strategy for preventing viral meningitis is to prevent viral
infection. Vaccination against measles and mumps (MMR vaccine) and
chickenpox (varicella-zoster vaccine) effectively protects children
against viral meningitis.3

Adherence to good-hygiene practices—thorough hand-washing, especially
after changing diapers, using the toilet, coughing, or blowing one’s
nose—is important for preventing transmission. Other key practices
include cleaning contaminated surfaces and avoiding the sharing of
utensils.

To prevent arbovirus infection, protection from mosquito bites by
wearing appropriate clothing and using insect repellent and bed nets
should be exercised, especially while traveling.44

To reduce the risk of LCMV infection, pregnant women should avoid
exposure to rats, house mice, and rodents such as hamsters and guinea
pigs. Any person who develops fever or other symptoms after contact with
a rodent should seek medical attention.25

Conclusion

Viral meningitis can affect individuals of any age. Pharmacists can
educate patients about the signs of meningitis and the importance of
determining the type of meningitis in a hospital setting to avoid
treatment delays in case the meningitis is bacterial. Pharmacists should
also inform patients that preventive measures, such as routine
vaccination and proper hygiene, can significantly reduce the risk of
viral meningitis.

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